Lung cancer causes more deaths worldwide than any other form of cancer (Goodman, G. E., Thorax 57:994-999 (2002)). In the United States, lung cancer is the primary cause of cancer death among both men and women. In 2002, the death rate from lung cancer was an estimated 134,900 deaths. Lung cancer is also the leading cause of cancer death in all European countries, and numbers of lung cancer-related deaths are rapidly increasing in developing countries as well.
The five-year survival rate among all lung cancer patients, regardless of the stage of disease at diagnosis, is only about 13%. This contrasts with a five-year survival rate of 46% among cases detected while the disease is still localized. However, only 16% of lung cancers are discovered before the disease has spread. Early detection is difficult as clinical symptoms are often not observed until the disease has reached an advanced stage. Currently, diagnosis is aided by the use of chest x-rays, analysis of the type of cells contained in sputum and fiberoptic examination of the bronchial passages. Treatment regimens are determined by the type and stage of the cancer, and include surgery, radiation therapy and/or chemotherapy. In spite of considerable research into therapies for this and other cancers, lung cancer remains difficult to diagnose and treat effectively. Accordingly, there is a great need for improved methods of detecting and treating such cancers.
Systematic analysis of mRNA and protein expression levels among thousands of genes has contributed to defining the molecular network of lung carcinogenesis (Meyerson and Carbone, J. Clin. Oncol. 23:3219-3226 (2005); Granville and Dennis, Cell Mol. Biol. 32:169-176 (2005)). For example, defects in both the p53 and RB/p16 pathways are common in lung cancer. Several other genes, such as K-ras, PTEN, FHIT and MYO18B, are genetically altered in lung cancers, though less frequently (Minna et al., Cancer Cell 1:49-52 (2002); Sekido et al., Annu. Rev. Med. 54:73-87 (2003); Yokota and Kohno, Cancer Sci. 95:197-204 (2004)). Although focusing on known genes and proteins has yielded useful information, previously unknown markers of lung cancer may also lend insight into the biology of lung cancer.
MicroRNAs (miRNAs) are a class of small, non-coding RNAs that control gene expression by hybridizing to and triggering either translational repression or, less frequently, degradation of a messenger RNA (mRNA) target. The discovery and study of miRNAs has revealed miRNA-mediated gene regulatory mechanisms that play important roles in organismal development and various cellular processes, such as cell differentiation, cell growth and cell death (Cheng, A. M., et al., Nucleic Acids Res. 33:1290-1297 (2005)). Recent studies suggest that aberrant expression of particular miRNAs may be involved in human diseases, such as neurological disorders (Ishizuka, A., et al., Genes Dev. 16:2497-2508 (2002)) and cancer. In particular, misexpression of miR-16-1 and/or miR-15a has been found in human chronic lymphocytic leukemias (Calin, G. A., et al., Proc. Natl. Acad. Sci. U.S.A. 99:15524-15529 (2002)).
The development and use of microarrays containing all known human microRNAs has permitted a simultaneous analysis of the expression of every miRNA in a sample (Liu, C. G., et al., Proc Natl. Acad. Sci. U.S.A. 101:9740-9744 (2004)). These microRNA microarrays have not only been used to confirm that miR-16-1 is deregulated in human CLL cells, but also to generate miRNA expression signatures that are associated with well-defined clinicopathological features of human CLL (Calin, G. A., et al., Proc. Natl. Acad. Sci. U.S.A. 101:1175-11760 (2004)).
Identification of microRNAs that are differentially-expressed in lung cancer cells would aid in diagnosing, prognosticating and treating lung cancer. Furthermore, the identification of putative targets of these miRNAs would help to unravel their pathogenic role. The present invention provides novel methods and compositions for the diagnosis, prognosis and treatment of lung cancer.